7. Project Summary/Abstract Alzheimer?s disease (AD) afflicts approximately 44 million people worldwide and is the most common cause of dementia in the elderly. There is an unmet medical need for the development of new Alzheimer?s disease therapeutics. Amyloid-? (A?) deposited in the Alzheimer?s diseased brain has been hypothesized to initiate a cascade of molecular changes leading to synaptic dysfunction, inflammation, and neuronal death. Therefore, designing therapies targeting A? and downstream events have become major strategies in Alzheimer?s disease drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone compounds (TPs) that show potent cell protection against A? toxicity. In our completed SBIR Phase I project, the lead compounds CP2 and TP70 were found to have high oral bioavailability, excellent blood?brain barrier permeability, and low toxicity. Administering compounds orally to young Alzheimer?s disease transgenic mouse models in a ?preventive trial? resulted in substantially reduced soluble and insoluble A? species in the brain and preserved memory and motor function. Furthermore, we have found that the lead TPs decreased both intraneuronal and extracellular A? aggregates as well as hyperphosphorylated tau (p-tau), restored axonal trafficking, and modulated hippocampal synaptic NMDA-mediated activity and plasticity ? these multiple synergistic cellular actions, rather than anti-A? toxicity alone, could be potential mechanisms underlying their in vivo effects. In this proposed SBIR Phase II project, our original Phase I investigative team with additional expertise in rodent brain imaging, clinical Alzheimer?s disease treatments, and non-GLP toxicity study providers, will conduct longitudinal studies of pharmacokinetics and pharmacodynamics (PK/PD) on the two aforementioned TP molecules in a new transgenic rat model of Alzheimer?s disease, in order to select the best lead as the IND candidate. We now choose the new TgF344-AD rat model for our studies because they exhibit accumulation of oligomeric A?, A??plaque formation, Tau pathology, behavioral Impairment, and neuronal loss that faithfully recapitulate hallmarks of human Alzheimer?s disease. We will achieve our goal by accomplishing the following Specific Aims: 1. Conduct PK/PD studies of CP2 and TP70 on TgF344-AD rats using our established assays/tests. The drug metabolism and PK studies include plasma and hepatocyte stability, plasma and brain protein binding, plasma and CSF concentrations, metabolite identification, P450 inhibition/induction, and excretion. In vivo efficacy especially cognition, brain imaging, and pathologic outcomes will be examined along with A? and tau protein biomarkers in CSF and brain to correlate with PD outcomes. 2. Preparation for IND-enabling studies. Conduct pilot safety pharmacology and non-GLP toxicology on the selected therapeutic candidates through contract service organizations to help make a go/no-go decision for IND-enabling studies in a Competing Renewal of SBIR Phase IIB or other programs. 3. Explore mechanisms of action underlying CP2 and TP70 efficacy in the transgenic rat model of Alzheimer disease. We will investigate CP2 and TP70 modulation of hippocampal synaptic, particularly NMDA receptor-mediated synaptic activity, plasticity and extrasynaptic NMDA receptors-mediated activity, and explore their links to other molecular and cellular actions Success in Phase II will lead to an IND candidate. Once an IND application is filed, it will attract non-government support and pharmaceutical partners for clinical development of this novel drug candidate for the treatment of Alzheimer?s disease.